The present invention relates to methods for formulating storage stable and easily rehydratable dried pharmaceutical compositions for administration to animals, especially for use as chemo-embolic compositions.
Embolisation therapy involves the introduction of an agent into the vasculature in order to bring about the deliberate blockage of a particular vessel. This type of therapy is particularly useful for blocking abnormal connections between arteries and veins, such as arteriovenous malformations (AVMs), and also for occluding vessels that feed certain hyper-vascularized tumours, in order to starve the abnormal tissue and bring about its necrosis and shrinkage. Examples of areas in which embolotherapy is increasingly being used are for the treatment of malignant hyper-vascular tumours such as hepatocellular carcinoma (HCC) and the treatment of uterine fibroids.
In the case of HCC it may be desirable to treat the tumour with an embolisation agent loaded with a chemotherapeutic agent. DC bead is an embolisation bead that can be loaded with doxorubicin prior to administration to a patient. It may be more convenient, however, if the beads could be supplied to the interventional radiologist with the doxorubicin already pre-loaded into the embolic agents. This saves time in preparation, handling of toxic drug and also the need to guess the amount of agent required for the procedure.
Due to the fact that many drugs, such as doxorubicin, are potentially unstable over time when in the hydrated form, an embolic adduct with pre-loaded drug may be lyophilised or freeze dried to remove excess water prior to terminal sterilization. The lyophilisation process results in the formation of a free flowing dry powder which is relatively stable during storage. This product is described in WO 2004/071495 A1.
In WO 2004/071495 A1 the polymer matrix is a cross-linked polyvinyl alcohol. Other particulate embolic materials are available, for instance based on alginates, albumin, gelatin, other synthetic polymers including PVA cross-linked with aldehydes, polyacrylates, polylactic- and polyglycolic acids. These may be in the form of irregular particles or, preferably, microspheres.
A number of other simple therapeutic compounds are being investigated in combination with microspheres for the embolization of other tumour types. Examples include irinotecan (WO-A-2006027567) and ibuprofen (WO-A-2006013376). In addition, newer drugs are becoming more complex in structure and there is a move away from simple molecular entities to much more complex entities which in some cases are of biological origin. These more complex molecular entities will probably be more unstable than corresponding simple molecular entities so the need for freeze drying of microspheres loaded with these species will probably be required to prolong their shelf-life.
One problem with freeze drying gels, e.g. hydrogels, or macroporous microspheres is that air pockets develop within the microspheres as the water is removed during the drying process. We have identified the fact that the presence of these air pockets is problematic when the dry beads are rehydrated. They can hinder the rate of hydration of the beads since the air needs to be exchanged with liquid for the bead to be fully hydrated. Since air is relatively hydrophobic and the aqueous liquids used for rehydration of the microspheres are hydrophilic, this process can be slow. In some cases, we have found hydration is totally inhibited by the presence of the air pockets within the micro spheres. One other consequence of the presence of trapped air inside the microspheres is the buoyancy of the microspheres is altered. Since the air is less dense than the liquid for rehydration the beads tend to float. This can be very problematic and can affect the potential to obtain an adequate suspension of the beads when hydrated, in for instance, a mixture of water and contrast agent. In order to deliver the microspheres an adequate suspension is required in the hydration medium for sufficient time to allow ease of handling and effective delivery through a micro-catheter. Homogeneous delivery of microspheres and suspending/contrast medium allows control of the dose of microspheres and of active.